title: Mouse mutants lacking the cation-independent mannose 6-phosphate/insulin-like growth factor II receptor are impaired in lysosomal enzyme transport: comparison of cation-independent and cation-dependent mannose 6-phosphate receptor-deficient mice.
abstract: Two proteins have been implicated in the mannose 6-phosphate-dependent transport of lysosomal enzymes to lysosomes: the 300kDa cation-independent and the 46kDa cation-dependent mannose 6-phosphate receptors (CI- and CD-MPRs). The mammalian CI-MPR also mediates endocytosis and clearance of insulin-like growth factor II (IGF-II). Mutant mice that lack the CD-MPR are viable, mice that lack the CI-MPR accumulate high levels of IGF-II and usually die perinatally, whereas mice that lack both IGF-II and CI-MPR are viable. To investigate the relative roles of the MPRs in the targeting of lysosomal enzymes in vivo, we analysed the effect of a deficiency of either MPR on lysosomal enzyme activities in animals lacking IGF-II. In CD-MPR-deficient mice, most activities were relatively normal in solid tissues and some were marginally elevated in serum. In CI-MPR-deficient mice, some enzyme activities were moderately decreased in solid tissues and multiple enzymes were markedly elevated in serum. Finally, total levels of serum mannose 6-phosphorylated glycoproteins were approximately 45-fold and approximately 15-fold higher than wild type in CI- and CD-MPR-deficient mice respectively, and there were specific differences in the pattern of these proteins when comparing CI- and CD-MPR deficient animals. These results indicate that while lack of the CI-MPR appears to perturb lysosome function to a greater degree than lack of the CD-MPR, each MPR has distinct functions for the targeting of lysosomal enzymes in vivo.
authors.affiliation: Center for Advanced Biotechnology and Medicine and Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, 679 Hoes Lane, Piscataway, NJ 08854, USA.
authors.forename: I
authors.initials: I
authors.lastname: Sohar
authors.forename: D
authors.initials: D
authors.lastname: Sleat
authors.forename: C
authors.initials: C
authors.lastname: Gong Liu
authors.forename: T
authors.initials: T
authors.lastname: Ludwig
authors.forename: P
authors.initials: P
authors.lastname: Lobel
mesh_terms: D000818:Animals; D001692:Biological Transport; D002412:Cations / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008168:Lung / Q000166:cytology / Q000201:enzymology; D008247:Lysosomes / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017527:Receptor, IGF Type 2 / Q000502:physiology*
chemical_list: D002412:Cations; D017527:Receptor, IGF Type 2